The syntheses of two tumor-associated carbohydrate antigens, Tn and TF, have been achieved using
glycal assembly and cassette methodologies. These synthetic antigens were subsequently clustered (c) and
immunoconjugated to a carrier protein (KLH or BSA) or a synthetic lipopeptide (pam) for immunological
study. Three Tn conjugates were used to vaccinate groups of mice, and all preparations proved to be
immunogenic. The Tn(c) covalently linked to KLH (27−KLH) plus the adjuvant QS-21 was the optimal
vaccine, inducing high median IgM and IgG titers against Tn(c) by ELISA. These antibodies were strongly
reactive with the Tn(c) positive human colon cancer cell line LS-C but not the Tn(c) negative colon cancer
cell line LS-B by FACS. The antibodies' reactivities with natural antigens were inhibited with synthetic Tn(c)
but not with structurally unrelated compounds. On the basis of these results, vaccines containing 27−KLH
and 30−pam plus QS-21 are being tested in patients with prostate cancer.
The complex carbohydrate molecule globo H hexasaccharide has been synthesized, conjugated to keyhole limpet hemocyanin, and administered with the immunologic adjuvant QS-21 as a vaccine for patients with prostate cancer who have relapsed after primary therapies such as radiation or surgery. Globo H is one of several candidate antigens present on prostate cancer cells that can serve as targets for immune recognition and treatment strategies. The vaccine, given as five subcutaneous vaccinations over 26 weeks, has been shown to be safe and capable of inducing specific high-titer IgM antibodies against globo H. Its immunogenicity was confirmed in prostate cancer patients with a broad range of stages and tumor burdens. Observations of several patients who had evidence of disease relapse restricted to a rising biochemical marker, prostate-specific antigen (PSA), indicated that a treatment effect could occur within 3 months after completion of the vaccine therapy. This effect was manifested as a decline of the slope of the log of PSA concentration vs. time plot after treatment compared with values before treatment. Five patients continue to have stable PSA slope profiles in the absence of any radiographic evidence of disease for more than 2 years. The concept of using PSA slope profiles in assessing early treatment effects in biological therapies such as vaccines awaits further validation in phase II and III trials. The use of a variety of lesser known candidate glycoprotein and carbohydrate antigens in prostate cancer serves as a focus for the development of a multivalent vaccine of the treatment of relapsed prostate cancer in patients with minimal tumor burden.
The carbohydrate antigen globo H commonly found on breast cancer
cells is a potential target for vaccine therapy. The objectives of this
trial were to determine the toxicity and immunogenicity of three
synthetic globo H-keyhole limpet hemocyanin conjugates plus the
immunologic adjuvant QS-21. Twenty-seven metastatic breast cancer
patients received five vaccinations each. The vaccine was well
tolerated, and no definite differences were observed among the three
formulations. Serologic analyses demonstrated the generation of IgM
antibody titers in most patients, with minimal IgG antibody
stimulation. There was significant binding of IgM antibodies to MCF-7
tumor cells in 16 patients, whereas IgG antibody reactivity was
observed in a few patients. There was evidence of complement-dependent
cytotoxicity in several patients. Affinity column purification
supported the specificity of IgM antibodies for globo H. On the basis
of these data, globo H will constitute one component of a polyvalent
vaccine for evaluation in high-risk breast cancer patients.
A safe synthetic conjugate vaccine in a trimer formation was developed that can break immunologic tolerance by inducing specific humoral responses. It seemed to affect the biochemical progression of the disease as determined by a change in PSA log slope.
Carbohydrate antigens such as GM2, GD2 and GD3 (gangliosides), Lewis(y) and globo-H (neutral glycolipids and glycoproteins), and Tn, TF and sTn (glycoproteins) are overexpressed in a variety of cancers. Antibodies against several of these carbohydrate antigens have been detected in sera from patients treated with cancer vaccines, and have been associated with a more favorable prognosis. Clinical responses have been reported after treatment with monoclonal antibodies against some of these antigens. Hence cell-surface carbohydrate antigens have been identified as suitable targets for immune attack by both active and passive immunotherapies. Different approaches have been adopted to induce immune responses against these carbohydrate antigens. These includes vaccination with whole or lysed tumor cells, purified or synthetic carbohydrates, immunogenic carbohydrate derivatives, or carbohydrates conjugated with immunogenic carriers and administered with immunological adjuvants. In the case of gangliosides, immunization with either whole tumor cells or cell lysates has only occasionally induced responses against carbohydrate antigens, and the antibodies were generally IgM antibodies of low titer. Compared with other methods of vaccination, conjugate vaccines have consistently induced the highest titer of IgM and IgG antibodies against gangliosides and other carbohydrate antigens. Preclinical and clinical studies with conjugate carbohydrate vaccines have induced IgM and IgG antibody responses capable of inducing complement-mediated cytotoxicity of tumor cells in vitro and associated with prolonged disease-free and overall survival in patients.
Passively administered and actively induced antibodies have been associated with the eradication of circulating tumor cells and micrometastases in mice and humans. We have identified a series of cell surface carbohydrate and peptide antigens on melanomas, sarcomas, and cancer of the breast, prostate. ovary, and lung tissues. We found that breaking tolerance toward these tumor antigens was best achieved using vaccines containing antigens chemically conjugated to keyhole limpet hemocyanin (KLH) plus a potent immunological adjuvant (QS-21). To date, by using this approach to vaccination. antibodies have been induced in patients against glycolipid antigens GM2, GD2, GD3, FucosylGM1, Globo H, and Lewis Y, and glycoprotein (mucin) antigens Tn, sialyl Tn. TF, and MUC1. More recently, in a comparative study we investigated the T cell response induced by MUCI-KLH conjugates. Although a MUC1-specific T cell response was not consistently detected in any patient, the role of KLH in orienting the cytokine environment was crucial. We were able to confirm that KLH in these conjugate vaccines induces a Th1 T cell response as demonstrated by the high anti-KLH INF-gamma secretion and the IgGI and IgG3 subclasses of this high titer IgG antibodies induced. Clinical trials using KLH conjugated glycolipid and glycoprotein vaccines, are currently ongoing. These range from phase I/II single antigens trials with glycosilated MUC1, polysialic acid, synthetic Fucosyl GMI and GD2, to phase II trials with a polyvalent vaccine containing six or seven antigens. Randomized phase II trials with polyvalent vaccines are planned for initiation in 2001-2002 in patients with ovarian, breast, and prostate cancer.
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